Molecular Regulation of Cardiomyocyte Differentiation

Abstract

The heart is the first organ to form during embryonic development. Given the complex nature of cardiac differentiation and morphogenesis, it is not surprising that some form of congenital heart disease is present in approximately one percent of newborns. The molecular determinants of heart development have received much attention over the past several decades. This has been driven in large part by an interest in understanding the etiology of congenital heart disease coupled with the potential of utilizing knowledge from developmental biology to generate functional cells and tissues that could be used for regenerative medicine purposes. In this review, we highlight the critical signaling pathways and transcription factor networks that regulate cardiomyocyte lineage specification in both in vivo and in vitro models. Special focus will be given to epigenetic regulators that drive the commitment of cardiomyogenic cells from nascent mesoderm and their differentiation into chamber-specific myocytes as well as regulation of myocardial trabeculation.

Sphingosine 1-phosphate receptor-1 in cardiomyocytes is required for normal cardiac development

“…In accord, more than 60 genes have been linked to ventricular noncompaction in human and mouse studies (Paige et al, 2015; Towbin et al, 2015; Wilsbacher and McNally, 2016). Disruption of endocardial and myocardial Notch signaling pathways after the onset of compaction leads to ventricular noncompaction, but in contrast to cardiomyocyte-specific S1pr1 deletion, these mutants display increased proliferation especially within the trabecular myocardium (D'Amato et al, 2016; Luxán et al, 2013).…”

“…Disruption of either trabeculation or compaction has important consequences; failure to undergo trabeculation results in growth arrest and embryonic lethality, while defective compaction results in left ventricular non-compaction cardiomyopathy. To date the molecular mechanisms that regulate the proliferation and differentiation required for trabeculation and compaction remain incompletely understood (Paige et al, 2015; Towbin et al, 2015; Wilsbacher and McNally, 2016). …”

Deciphering the Epigenetic Code of Cardiac Myocyte Transcription

“…Factors explaining the remaining transcriptional variability include varying activity of enhancers 43 and transcription factors. 44 This tight link of chromatin state and transcriptional activity can only be uncovered in cell-type-specific data sets.…”

Building and re-building the heart by cardiomyocyte proliferation

“…The first wave of cardiomyocyte precursors forms a crescent near the head folds that subsequently fuses at the midline to form the primitive heart tube (Buckingham et al, 2005). As the heart tube forms, de novo cardiomyocyte creation occurs both from the differentiation of these precursors and from a second heart field in the pharyngeal mesoderm (Kelly et al, 2001;Mjaatvedt et al, 2001;Waldo et al, 2001; reviewed by Kelly et al, 2014;Paige et al, 2015). Multiple studies in chick have revealed little evidence for cardiomyocyte division occurring during these early stages (Sissman, 1966;van den Berg et al, 2009).…”